Spike mutations in SARS-CoV-2 AY sublineages of the Delta variant of concern: implications for the future of the pandemic

Daniele Focosi*,1 , Fabrizio Maggi2,3 , Scott McConnell4 & Arturo Casadevall4 1North-Western Tuscany Blood Bank, Pisa University Hospital, Pisa, Italy 2Department of Medicine & Surgery, University of Insubria, Varese, Italy 3Laboratory of Microbiology, ASST Sette Laghi, Varese, Italy 4Department of Medicine, Johns Hopkins School of Public Health & School of Medicine, Baltimore, MD 21287, USA *Author for correspondence: daniele.focosi@gmail.com

Editorial Focosi, Maggi, McConnell & Casadevall is to date the only correlate of immunity and hence the target of neutralizing antibody-based therapeutics (either monoclonal antibodies or convalescent plasma) and preventive vaccines.
Supplementary Table 1 summarizes the 43 AY sublineages (out of 209) harboring Spike mutations, with details on the expected impact of the five sublineages harboring mutations within the Spike receptor-binding domain of subunit S1 (i.e., amino acids 319-541).
Of interest, S255F which occurs in AY.106 was also recovered from an immunocompromised host in the absence of neutralizing antibody-based therapeutics [13], suggesting within-host evolution.
While Delta has clearly outcompeted Alpha and Gamma [14], Delta is unlikely to be the ultimate SARS-CoV-2 strain. Reports from South Africa, Scotland and Denmark suggest that the Omicron VOC is more transmissive and able to rapidly misplace Delta [15]: whether lockdown and travel restriction will be able to confine Omicron remains unknown, but experience with the former VOCs suggests containment is likely to be futile, especially for a variant that has a higher basic reproduction number. Supplementary Figure 1 shows how the R 0 of SARS-CoV-2 has grown from the original Wuhan strain (2.4-3.4) to Alpha (4)(5) to Delta (5)(6)(7)(8), and how there is still theoretical room for getting values as high as for measles virus (12)(13)(14)(15)(16)(17)(18). It can also be expected that with massive circulation Omicron will split into many different sublineages, as it has happened with former VOCs Alpha (eight sublineages), Beta (five sublineages), Gamma (20 sublineages) and Delta (125 sublineages). Even when vaccines inducing sterilizing immunity would become available, the herd immunity threshold could be exceedingly high to be achieved if the elicited immunity is shortlasting.
One of the major lessons from the first 2 years of the pandemic is that in westernized societies modern medicine has saved the lives of millions of individuals at the price of compromised immunity and produced a population of immunocompromised patients who provide vulnerable hosts where SARS-CoV-2 can replicate for prolonged periods of time, resulting in within-host variation. This is an unprecedented landscape for pandemics, which could alter the trajectory of natural evolution. Repeated emergence of Spike variants largely deviating from the originator lineage can hence be anticipated for the coming years, as previously happened for VOCs (Alpha [23 mutations [16]] and Omicron [32 mutations [15]]) or lineages that poorly propagated (e.g., A.VOI.V2 [11 Spike mutations [17]] B.1.1.318 [14 mutations [18]] and B.1.616 [ten mutations [19]]), making clear that the number of Spike mutations per se is not a predictor of SARS-CoV-2 fitness.
With mounting evidence suggesting that vaccine efficacy declines significantly after as few as 6 months from the second dose, and considering that sterilizing immunity is not achievable with the current generation of nonmucosal vaccines (leaving room for transmission by vaccines and preventing herd immunity to the immunocompromised nonresponders), sudden and unpredictable Spike evolution calls for urgent research into new different types of vaccines. While it is unclear to date whether whole virus vaccines would provide better correlates of immunity, this is a road that is worth being explored in addition to Spike-only-based vaccines.

Future perspective
Although, the early successes with vaccines and antibody-based therapies in the 1st year of the pandemic gave rise to a premature optimism that the pandemic could be contained in the foreseeable future, it is now clear that humanity might be in for a long struggle with SARS-CoV-2, given its remarkable ability to evolve via single mutations, insertions, deletions or recombination. This is difficult news for COVID-19-weary populations of the world who are entering their 3rd year of the pandemic. However, we believe that public health authorities need to have a frank discussion with the public, admitting the likelihood of the protracted struggle that will see successes, reverses, continued disruption to the norms of everyday life and suffering for many in the form of disease and death. The public in turn needs to be reassured that the way out of this calamity is by continued investment in basic science, clinical research and public health, since the road to normality with an endemic SARS-CoV-2 requires better vaccines and more effective therapies to prevent infection and disease and reduce morbidity and mortality, respectively.